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RdRPs are essential in virus life cycle due to their central role in viral genome replication\/transcription processes. However, their contribution in host adaption has not been well documented. By solving the RdRP crystal structure of the tick-borne encephalitis virus (TBEV), a tick-borne flavivirus, and comparing the structural and sequence features with mosquito-borne flavivirus RdRPs, we found that a region between RdRP catalytic motifs B and C, namely region B-C, clearly bears host-related diversity. Inter-virus substitutions of region B-C sequence were designed in both TBEV and mosquito-borne Japanese encephalitis virus backbones. While region B-C substitutions only had little or moderate effect on RdRP catalytic activities, virus proliferation was not supported by these substitutions in both virus systems. Importantly, a TBEV replicon-derived viral RNA replication was significantly reduced but not abolished by the substitution, suggesting the involvement of region B-C in viral and\/or host processes beyond RdRP catalysis. A systematic structural analysis of region B-C in viral RdRPs further emphasizes its high level of structure and length diversity, providing a basis to further refine its relevance in RNA virus-host interactions in a general context.<\/jats:p>","DOI":"10.1093\/nar\/gkaa1250","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T12:52:37Z","timestamp":1608036757000},"page":"1567-1580","source":"Crossref","is-referenced-by-count":33,"title":["Crystal structure of a tick-borne flavivirus RNA-dependent RNA polymerase suggests a host adaptation hotspot in RNA viruses"],"prefix":"10.1093","volume":"49","author":[{"given":"Jieyu","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuping","family":"Jing","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfu","family":"Yi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8895-3679","authenticated-orcid":false,"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"},{"name":"Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8264-7523","authenticated-orcid":false,"given":"Peng","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei 430071, China"},{"name":"Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"key":"2021022123595915600_B1","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1099\/0022-1317-82-8-1867","article-title":"Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography","volume":"82","author":"Gaunt","year":"2001","journal-title":"J. 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